Many drugs mediate their effects on cells by interacting with (e.g., binding) nucleic acid sequences in cells. Interactions of drugs with nucleic acid sequences in cells (e.g., DNA of a cancerous cell) can stop cellular proliferation or cause cell death, thereby halting the progression of a disease state. However, many drugs employed to treat diseases are either insufficiently soluble in aqueous solutions or have adverse side effects, such as the death of healthy cells, because of the lack of suitable substances to deliver drugs to a cell or organism (e.g., mammal) requiring treatment.
There have been many attempts to overcome problems generally associated with drug delivery. For example, macromolecular drug-carriers, which most commonly are water-soluble macromolecules with chemically associated drug molecules, often are employed to prolong drug circulation, limit renal clearance, increase drug accumulation in target tissues or cells, and to decrease drug concentration in normal tissues. Several model and prototype carriers of this type have been developed. Potentially, these carriers can be as small as 5-10 nanometers (nm), but depending on the drug structure and content, they often form larger (20-50 nm) associates. Carriers of this type are intended to act, essentially, as pro-drugs, the drug substance as a result of degradation of the drug-carrier bond. Some carriers of this type have been targeted to cancer cell markers. Examples of this class of drug-carriers are: dextran-mitomycin conjugates; HPMA-doxorubicin conjugates with enzyme-degradable peptide bonds between the drug molecule and the backbone polymer; doxorubicin-Fab conjugates with pH-sensitive bonds between doxorubicin molecules and the Fab. Although potentially useful, carriers of this type have at least two potential drawbacks.
First, drug release via degradation of the drug-carrier bond generally is irreversible. Thus, drug released from the carrier will circulate in the body independently of the carrier, which may reduce the efficacy of drug delivery. Drug release via enzyme-dependent or pH-dependent hydrolysis has been reported to improve the ratio of drug activity in the target relative to normal tissues. However, expression of enzymes, such as proteases, in tumors and other pathologies is highly variable, which makes predictability of release rate of the drug difficult. Enzyme-independent biodegradation, on the other hand, can occur in both pathological and normal tissues.
A second problem relates to exposure to the environment of drug molecules attached to the macromolecular backbone. This can result in cross-interaction of drug moieties with formation of intramolecular and intermolecular micelles, interactions with tissue components altering drug-carrier adduct biodistribution, and other undesirable effects. These effects are expected to be partially suppressed via “steric protection,” or modification of the carrier backbone with hydrophilic polymer chains such as, for example, polyethyleneglycol, dextran, or PHF (polyhydroxymethylethylene hydroxymethylformal). However, in sterically protected carriers, enzyme access to enzyme-sensitive drug-carrier bonds also may be suppressed.
Another attempt to overcome problems associated with drug delivery includes combination of drugs with microparticles and emulsions. Microparticles and emulsions were developed as an alternative where the drug molecules are not bound chemically, but rather are adsorbed on, or dissolved in, the material of the carrier. However, particles and emulsions do not circulate in vivo long enough and accumulate in the reticuloendothelial system (RES) and other organs, unless the particle (droplet) surface is modified with a hydrophilic polymer, such as PEG. The overall size of sterically protected particles (droplets) is usually above about 25 nm. Major problems in the development of such carriers include the fact that (1) the emulsions generally are relatively unstable and change (e.g. coalesce) in storage; (2) high-scale production of both submicron particles and emulsions typically is difficult; and (3) drug molecules released from the particles or droplets will circulate independently of the carrier. Emulsions and most particles are not suitable for transport of hydrophilic drugs.
A specific development in drug delivery was employment of micelles, which were developed as “self-assembling” drug carriers similar to particles and emulsions. They are made of surfactants, which are usually block copolymers, where one of the blocks is hydrophilic, and the other hydrophobic. The total hydrodynamic size of the micelles usually is 10-30 nm. The hydrophobic drug molecules either are incorporated into the hydrophobic core or, alternatively, chemically conjugated with one of the blocks and form the hydrophobic core. Some of the problems in the development of such carriers are similar to those described above. In addition, none of these carriers can reabsorb specifically the released drug; drug release rate is difficult to control, and amphiphylic components can produce toxic effects. These carriers are not suitable for transport of hydrophilic drugs.
Still another attempt includes encapsulation of drugs in the aqueous compartments of liposomes, which are vesicles, typically having a diameter in a range of between about 50 and about 1000 nm. However the efficacy of drug encapsulation and the potential to control drug delivery by incorporation into liposomes can be problematic. For example, drug release from liposomes generally is irreversible. Further, liposome penetration into tumors or tumor zones that have relatively low vascular permeability often is poor. Also, there are many problems associated with high-volume production and storage of liposomal preparation that present significant technical challenges.
Other systems employed to bind drugs for delivery to a cell or an organism have similar drawbacks. Thus, there is a need for a method to deliver drugs that minimize or overcome the above-referenced problems.